Histamine release inhibitor

ABSTRACT

The present invention provides a histamine release inhibitor comprising a pectin or a salt thereof or a pectin hydrolysate as an active ingredient, and a pharmaceutical composition, a cosmetic, and food and drink comprising the inhibitor.

TECHNICAL FIELD

The present invention relates to a histamine release inhibitor capableof preventing and/or treating diseases such as allergic rhinitis, atopicdermatitis, urticaria, bronchial asthma, peptic ulcer, and pollinosis,and to a pharmaceutical composition, a cosmetic, and food and drinkcomprising the inhibitor.

BACKGROUND ART

Histamine plays an important role in inflammation and immediate allergicdiseases. Immunological stimulation induces degranulation of mast cellsand basocytes, during which in vivo chemotransmitters such as histamine,leukotrien, and serotonin are released into the blood.

Among the above in vivo chemotransmitters, histamine in particular hasbeen the most studied. Histamine released in blood binds to thehistamine receptors of various organs, inducing symptoms such asincreased blood vessel permeability, smooth muscle atrophy, andincreased mucous secretion. As a result, it is known that diseases suchas allergic rhinitis, atopic dermatitis, urticaria, bronchial asthma,peptic ulcer, and pollinosis may be induced (see e.g., White, M. V. etal., “Journal of Allergy and Clinical Immunology,” 1990, 86: pp.599-605).

Furthermore, it has been reported that when bronchoalveolar lavage isperformed for a bronchial asthma patient, the resulting histamineconcentration in a washing solution becomes significantly higher thanthat of a normal healthy person (see e.g., Casale, T. B. et al.,“Journal of Clinical Investigation,” 1987, 79: pp. 1197-1203).

Hence, to inhibit allergies and inflammation, it is necessary to inhibitin vivo chemotransmitters such as histamine from being released into theblood.

Currently, the two following methods are employed for treating allergicdiseases caused by histamine. A 1st method is to block histaminereceptors by administering a chemically synthesized product referred toas an antihistamic agent. A 2nd method is to inhibit histamine releasefrom mast cells by administering a mast cell histamine releaseinhibitor.

However, taking an antihistamine agent according to the former method isproblematic in that sleepiness, vertigo, or dullness may be caused or inthat a side effect such as arrhythmia may be caused. By taking such anantihistamine agent, diseases can be temporarily treated, but continuoustaking of such an agent for the purpose of prevention is dangerous. Inthe case of the latter method, experiments at the cellular level havebeen conducted using a histamine release inhibitor in mast cells.However, when the mast cell histamine inhibitor is actually taken orapplied, it is problematic in that it is unclear whether or not it istransferred in the blood and directly acts on mast cells.

Therefore, histamine release inhibitors that are safe and have beenconfirmed to have a definite effect when they are taken or applied aredesired for preventing and/or treating allergic diseases.

In the meantime, the association of diet with the incidence of chronicnonspecific lung diseases such as asthma, bronchitis, and pulmonaryemphysema has been investigated for 25 years (1960-1985) in a study ofthe inhabitants of the area of Zutphen, in the Netherlands (see Miedema,I. et al., “American Journal of Epidemiology,” 1993, 138: pp. 37-45). Asa result, no significant differences have been observed between theintake of vegetables and fish and the onset of the above chronicnonspecific lung diseases. However, the intake of fruits inhibited theonset of these diseases, confirming a negative correlation between theintake of fruits and the above chronic nonspecific lung diseases(relative risk of 0.73: 95% confidence interval ranging from 0.53 to0.99). In particular, when persons taking 70 g or more of apple or pearper day were compared with persons taking 14 g or less of the same, therelative risk was found to be 0.63 (95% confidence interval ranging from0.45 to 0.88). Accordingly, the risk of chronic nonspecific lungdiseases such as asthma can be reduced by 37% by the intake of apples orpears. This has revealed that chronic nonspecific lung diseases such asbronchial asthma can be prevented by the daily intake of largequantities of fruit (particularly apple and pear). However, this reportdoes not disclose about which ingredients contained in fruits, includingapples and pears, are effective in the prevention of chronic nonspecificlung diseases such as bronchial asthma.

Furthermore, Yamada et al., conducted an animal experiment using ratswherein the dietary effects obtained by the intake of water-solubledietary fibers such as guar gum, glucomannan, and high methoxyl pectinon serum lipid concentration and IgA production were examined andcompared with those of insoluble cellulose. It was reported that serumIgA concentration was increased by the intake of water-soluble dietaryfibers (see Yamada, K. et al., “Bioscience, Biotechnology, andBiochemistry,” 1999, 63: pp. 2163-2167). However, this report does notdescribe the relationship between pectin and IgE antibody productioninvolved in allergic reaction and does not disclose any effect of pectinon histamine production at all.

SUMMARY OF THE INVENTION

An object of the present invention is to provide: a histamine releaseinhibitor that is safe if it is taken daily and is capable of preventingand/or treating diseases such as allergic rhinitis, atopic dermatitis,urticaria, bronchial asthma, peptic ulcer, and pollinosis; and apharmaceutical composition, a cosmetic, and food and drink comprisingthe inhibitor.

As a result of intensive studies to achieve the above object, we havefound that pectin that is already widely used as a food material hasaction to lower histamine concentration in blood, and thus we havecompleted the present invention.

The present invention provides the following (1) to (9).

(1) A histamine release inhibitor, comprising a pectin or a salt thereofor a pectin hydrolysate as an active ingredient.

(2) The histamine release inhibitor of (1), wherein the pectin is a highmethoxyl pectin having an esterification degree of 50% or more and 90%or less.

(3) The histamine release inhibitor of (1), wherein the pectin is a lowmethoxyl pectin having an esterification degree of 3% or more and lessthan 50%.

(4) The histamine release inhibitor of (1), wherein the pectinhydrolysate is oligogalacturonic acid and/or polygalacturonic acid witha polymerization degree between 2 and 100.

(5) The histamine release inhibitor of (1), wherein the pectinhydrolysate is an oligosaccharide comprising 1 type or 2 or more typesselected from the group consisting of galacturonic acid, rhamnose,arabinose, xylose, fucose, and galactose as a constituent.

(6) The histamine release inhibitor of any one of (1) to (5), which isfor preventing and/or treating allergic rhinitis, atopic dermatitis,urticaria, bronchial asthma, peptic ulcer, and/or pollinosis.

(7) A pharmaceutical composition, comprising the inhibitor of any one of(1) to (6).

(8) A cosmetic, comprising the inhibitor of any one of (1) to (6).

(9) Food and drink, comprising the inhibitor of any one of (1) to (6).

This specification includes part or all of the contents as disclosed inthe specification and/or drawings of Japanese Patent Application No.2002-275368, which is a priority document of the present application.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an example of the structure of an apple pectin.

FIG. 2 shows periods of pectin intake and timing of blood collection.

FIG. 3 shows fluctuations in histamine concentration in the blood ofeach subject during an experiment period.

BEST MODE OF CARRYING OUT THE INVENTION

The present invention will be further described in detail as follows.

The pectin having action to inhibit histamine release of the presentinvention is also referred to as a pectic substance that is aconstituent of a plant cell wall and is an acidic polysaccharide broadlyexisting in nature. The chemical structure of pectin (pectic substance)is composed of the main chain (rhamnogalacturonan) wherein:D-galacturonic acids are linked by α-1,4 bonds to form polygalacturonicacid (polygalacturonan) and L-rhamnose that is linked by α-1,2 bonds toa part of the polygalacturonic acid and thus coexists therewith; andside chains composed of neutral sugars such as arabinose, xylose,fucose, rhamnose, and galactose linked to the main chain, therebyforming a pectinate structure. The side chains account for approximatelyaround 10% of a pectin (pectic substance). Most of the side chains arelinked to position 4 of rhamnose and may be also linked to parts ofgalacturonic acids. In addition, as an example of a pectin structure,FIG. 1 shows an example of an apple pectin structure.

Examples of the pectin (pectic substance) of the present inventioninclude protopectin, pectinic acid, pectic acid, and polygalacturonicacid. “Protopectin” is water-insoluble substance composed of cellulose,hemicellulose, lignin, protein, and the like linked to pectin in a planttissue. The protopectin is solubilized by maturation (enzyme) to becomepectinic acid. “Pectinic acid” is known as pectin in a narrow sense andis polygalacturonic acid of chain molecule (also referred to aspolygalacturonan) composed of D-galacturonic acids polymerized by α-1,4bonds and carboxyl groups that compose a part of the polygalacturonicacid and are partially methyl-esterified to be methoxyl groups. Hence,pectinic acid is a water-soluble substance with relatively low methoxylgroup content. Furthermore, “pectic acid” is polygalacturonic acidcomposed of D-galacturonic acids polymerized by α-1,4 bonds. That is,this is pectinic acid containing no (or almost no) methoxyl groups.

Pectin is generally classified into high methoxyl pectin (also referredto as HM pectin) with an esterification degree of 50% or more and 100%or less, and low methoxyl pectin (also referred to as LM pectin) with anesterification degree of 0% or more and less than 50% according to themethyl-esterification ratio of carboxyl groups of galacturonic acids.However, types of pectin to be used in the inhibitor of the presentinvention are not limited by esterification degree. Any pectin such ashigh methoxyl pectin, low methoxyl pectin, or a mixture thereof can beused.

However, for use in the present invention, pectin with an esterificationdegree between 3% and 90% is preferable. High methoxyl pectin exists ina form resembling that of pectin existing in fruits, so that highmethoxyl pectin with an esterification degree between 50% and 90% ismore preferable, and high methoxyl pectin with an esterification degreebetween 65% and 85% is particularly preferable.

Furthermore, the molecular weight of pectin is also not particularlylimited, but pectin with a low molecular weight is preferable in orderto enhance solubility when it is added to a pharmaceutical composition,a cosmetic, or food and drink. For example, the origin of the pectin ofthe present invention is not particularly limited. The pectin may bederived from nature or it may be synthetic pectin. Particularlypreferred pectins are derived from pectin-rich origins that aregenerally used as raw materials for pectin production, such as pericarpsof citrus fruits, strained lees of apples, corn bran, wheat bran, sugarbeet fibers, soybean fibers, and defatted rice bran.

Pectin production methods are not particularly limited. Generally,pectin production methods that are employed in industrial production canbe implemented. For example, protopectins contained in strained lees ofapples or pericarps of citrus fruits are hydrolyzed in ahigh-temperature acidic solution, followed by compression andfiltration. The obtained filtrate is concentrated, pectin isprecipitated with alcohol, and then washing, drying, and grinding can beconducted, thereby obtaining pectin in the form of powders. The thusobtained pectin is treated with acid, enzyme, or ammonia fordemethylation to give low methoxyl pectin with a low esterificationdegree (“New Edition, Food Science and Technology Encyclopedia”(“Shin-ban Shokuhin Kogyo So-go Jiten” (edited by the Japanese Societyfor Food Science and Technology, KORIN Publishing Co., Ltd.))). Inaddition, for a laboratory-scale method of extracting pectin, “PecticSubstance, Protein•Nucleic acid•Enzyme” (Junichiro Ozawa, 15: pp.888-894 (1970)) can be referred to.

Furthermore, pectin marketed as a food additive such as a gelatinizer, astabilizer, or a thickener can also be directly utilized. Examples ofhigh methoxyl pectin include UNIPECTINE type HM 1, UNIPECTINE type PG109C, UNIPECTINE type SS 150, and UNIPECTINE type AYD 30 (all of whichare produced by SKW BIOSYSTEMS) and GENU pectin type YM-150-LJ, GENUpectin type D Slow Set, and GENU pectin type BETA (all of which areproduced by CP Kelco). Furthermore, examples of low methoxyl pectininclude UNIPECTINE type OF 805, UNIPECTINE type AMP 285, UNIPECTINE typeOB 700, and UNIPECTINE type AYD30 (all of which are produced by SKWBIOSYSTEMS), and GENU pectin type LM-12-1CG (produced by CP Kelco).

Moreover, the pectin obtained as described above may be a pectin whereincarboxyl groups form salts with various types of alkali such as sodium,calcium, and potassium.

In the present invention, a pectin hydrolysate can also be used as anactive ingredient of the histamine release inhibitor. For example, apectin hydrolysate can be obtained by hydrolysis of pectin using anenzyme such as 1% pectinase or a cell wall degrading enzyme or byhydrolysis of pectin by causing acid or alkali to act thereon. Anexample of 1% pectinase is polygalacturonase that can be caused to actat 37° C. for 4 hours at pH 4.5. Furthermore, examples of a cell walldegrading enzyme that is preferably used in the present inventioninclude Macerozyme (produced by YAKULT PHARMACEUTICAL IND. CO., LTD) andPectriase (produced by Kikkoman Corporation) that can be caused to actat 37° C. for 4 hours at pH 5.5. As acid, for example, 1N to 2Nhydrochloric acid or sulfuric acid can be used and caused to act at 100°C. for 3 hours. Moreover, as alkali, for example, 0.05N sodium hydroxidecan be used and caused to act at 0° C. for 24 hours. However, thesehydrolysis conditions do not limit the present invention.

The pectin hydrolysate of the present invention can be obtained by theabove hydrolysis using an enzyme or acid or alkali. Examples of thehydrolysate include oligogalacturonic acid and/or polygalacturonic acidwith various polymerization degrees. Furthermore, by purificationthrough gel filtration, ultrafiltration, or the like, oligogalacturonicacid and/or polygalacturonic acid with a desired polymerization degreecan be obtained. Of these, oligogalacturonic acid and/orpolygalacturonic acid with a polymerization degree ranging from 2 to 100is preferable and in particular, oligogalacturonic acid with apolymerization degree ranging from 2 to 10 is preferable. In addition,such oligogalacturonic acid and/or polygalacturonic acid may be in astate wherein the side chain portion composed of neutral sugars such asarabinose, xylose, fucose, rhamnose, and galactose and portions of theside chain portion are bound depending on the site and the strength ofhydrolysis by an enzyme or acid or alkali.

Furthermore, an oligosaccharide comprising 1 type or 2 or more typesselected from the group consisting of galacturonic acid, rhamnose,arabinose, xylose, fucose, and galactose as a constituent can beobtained by sufficiently carrying out hydrolysis using an enzyme or acidor alkali. Such oligosaccharides are also included in the hydrolysate ofthe present invention. Of these, in particular, an oligosaccharide ofarabinose is particularly preferred.

In addition, commercially available products of these oligosaccharides,the above oligogalacturonic acid, and the above polygalacturonic acidcan also be utilized. For example, an oligosaccharide of arabinose ismarketed by Megazyme International Ireland, Ltd.

Whether or not pectin has action to lower histamine concentration inblood can be confirmed by, for example, letting subjects experienceintake of the pectin for 3 weeks, collecting blood before the start ofintake, at the end of intake, and 2 weeks after the end of intake, andmeasuring histamine concentration in blood. By this method, we haveconfirmed that histamine concentration in blood is significantly loweredby the intake of pectin.

As described above, a pectin or a salt thereof or a pectin hydrolysatehas a feature of lowering histamine concentration in blood. Hence, thehistamine release inhibitor comprising a pectin or a salt thereof or apectin hydrolysate as an active ingredient can be directly administeredwhen it is used for preventing and/or treating diseases such as allergicrhinitis, atopic dermatitis, urticaria, bronchial asthma, peptic ulcer,and pollinosis.

Furthermore, the histamine release inhibitor comprising a pectin or asalt thereof or a pectin hydrolysate as an active ingredient can bemixed with pharmaceutically acceptable various carriers and otheringredients to produce a pharmaceutical composition for preventingand/or treating diseases such as allergic rhinitis, atopic dermatitis,urticaria, bronchial asthma, peptic ulcer, and pollinosis by a knownmethod.

Examples of the dosage form of a histamine-release-inhibitingpharmaceutical composition include oral agents such as tablets, powders,granules, capsules, and syrups, parenteral agents such as injections,and external preparations such as ointment, cream, lotion, and gel.Formulation can be carried out by a standard method. Regarding the formof administration, the composition can be administered to animalsincluding humans, orally, parenterally (e.g., intravenous,intra-arterial, intramuscular, intraperitoneal, or subcutaneousadministration), via rectum, nasal cavity, eyes, or the like, or byapplication to skin. The form of administration is not particularlylimited. However, there may be a case where long-term administration isrequired in addition to preventive administration. When these cases aretaken into consideration, oral administration or application to skin ispreferable because of convenience in administration and low mental andphysical burdens to patients.

As long as there are no problems in simultaneous administration, otherknown antiinflammatory agents and other known allergy inhibitors can beused in combination as other ingredients.

As a pharmaceutically acceptable carrier to be used for thepharmaceutical composition of the present invention, carriers that aregenerally used as materials for preparations, such as excipients,extending agents, binders, moistening agents, disintegrating agents,surfactants, lubricants, dispersing agents, buffers, preservatives, orthe like are appropriately combined and prescribed, so as to allowproduction of the pharmaceutical composition. If necessary, additivessuch as antiseptics, antioxidants, colorants, corrigents, aromatics, andcoatings can also be used.

Specifically, as examples of a solid carrier, starch, lactose,carboxymethyl-cellulose, corn starch, light anhydrous silicic acid,crystalline cellulose, dextrin, hydroxypropylcellulose,polyvinylpyrrolidone, magnesium stearate, calcium stearate, or talc canbe used. Furthermore, as examples of a liquid carrier, distilled water,saline, glucose aqueous solution, ethanol, propylene glycol, or thelike, sesame oil, or corn oil can be used. These carriers may beappropriately selected depending on the dosage form or the form ofadministration.

The dose of the pectin or the salt thereof or the pectin hydrolysate ofthe present invention may be any dose, as long as it can inhibit therelease of histamine. Such dose can be administered once or at severalseparate instances; that is, once to several instances per day. This ispreferably determined appropriately depending on purposes for use(treatment and/or prevention), age and weight of subjects,administration methods, and the like.

Furthermore, by adding the histamine release inhibitor comprising apectin or a salt thereof or a pectin hydrolysate as an active ingredientto a cosmetic as an ingredient, a cosmetic for preventing diseases suchas allergic rhinitis, atopic dermatitis, urticaria, bronchial asthma,peptic ulcer, and pollinosis, or alleviating the symptoms of thesediseases can be obtained. In the present invention, examples of acosmetic include toilet water, emulsions, cream, and bath agents, butare not limited thereto. In these cosmetics, if necessary, raw materialsthat are generally used for cosmetics, such as oil, moisturizing agents,ultraviolet absorption agents, antioxidants, and preservatives can beappropriately compounded therein. Moreover, other anti-inflammatory rawmaterials that are generally used for cosmetics, such as glycyrrhizicacid and diphenhydramine hydrochloride, can also be added if necessary.

Furthermore, by adding the histamine release inhibitor of the presentinvention to food and drink as a raw material, food and drink havingactivity of inhibiting histamine release can be provided. Examples ofsuch food and drink include: beverages such as refreshing drinks,carbonated drinks, lactic acid beverages, juice, and nutritional drinks;jam, jelly, cream, ice cream, and sweet stuff and ice such as candies,buiscuits, pudding, crunch chocolate, and cornflakes; dairy productssuch as yogurt; and seasonings such as mayonnaise and dressing, but theyare not limited thereto. The compounding ratio of the histamine releaseinhibitor of the present invention in food and drink is not particularlylimited, and can be appropriately determined according to the physicalproperties and the like of food and drink to which the inhibitor isadded. The food and drink of the present invention contain large amountsof the histamine release inhibitor, which is impossible to obtain bydirect intake of fruits alone, so that the food and drink are veryeffective for preventing diseases such as allergic rhinitis, atopicdermatitis, urticaria, bronchial asthma, peptic ulcer, and pollinosis,and alleviating the symptoms of these diseases.

No upper limits are particularly determined for the dose, the amountused, or the intake of the above pharmaceutical composition, cosmetic,or food and drink, because pectin is classified as belonging to a classof food additives for which it is not required by FAO/WHO to determineallowable intake per day. According to the forms for use, purposes,conditions of patients, and the like, the dose (intake) can beappropriately determined. For example, in the case of oraladministration or intake, a dose (intake) between 0.1 g and 50 g perday, preferably a dose (intake) between 6 g and 36 g per day, and morepreferably a dose (intake) between 8 g and 20 g per day can be employed.

In the case of pharmaceutical compositions for parenteral administrationand cosmetics, the content of the histamine release inhibitor of thepresent invention can be determined to range from 0.0001% to 50.0% (w/w)in a preparation, is preferably 0.001% or more, and is furtherpreferably 0.01% or more, and is even further preferably 0.1% or more.The upper limit is determined depending on the physical and chemicalproperties of preparations. In addition, when the inhibitor is containedin a bath agent, the agent may be formulated to achieve the aboveconcentration range at the time of use.

No considerable side effects have been reported concerning the histaminerelease inhibitor of the present invention at this time. Hence,cosmetics and food and drink comprising the histamine release inhibitorcan be continuously used for or taken by animals including humans forthe purpose of preventing and/or treating diseases such as allergicrhinitis, atopic dermatitis, urticaria, bronchial asthma, peptic ulcer,and pollinosis.

Examples will be shown below to explain the present invention in detail,but are not intended to limit the present invention.

EXAMPLE 1 Confirmation of Changes in Blood Histamine Concentration Dueto Pectin Intake

Subjects were asked to take pectin for 3 weeks. Blood was collectedbefore the start of intake, at the end of intake, and 2 weeks after theend of intake, and histamine concentration in blood was measured fordetermination.

The pectin used herein was granular pectin that was appropriate forintake and had been prepared based on the method for producing athickening polysaccharide material as disclosed in the JP PatentPublication (Kokai) 2000-014336 A. Specifically, an apple-derived highmethoxyl pectin powder product, Apple Pectin HM-1 (with a pectin contentof 90.5% and an esterification degree between 72 and 76) (produced bySKW BIOSYSTEMS, France) and anhydrous crystal glucose were compounded ata 1:1 ratio to produce mixed powders, and then the powders were directlyheated under anhydrous conditions. The thus obtained pectin granuleswere used for this experiment.

Subjects (14 adults: 47 years old on average, 25 to 68 years old, 11males and 3 females) were asked to take 22.2 g of pectin granules(equivalent to 9.99 g of pectin) per day as a standard for a period of 3weeks. Blood was collected before the start of intake, at the end ofintake, and 2 weeks after the end of intake, and plasma histamineconcentration was measured. In addition, the experiment was conductedfor a period of 7 continuous weeks, including the 2 weeks before thestart of intake. During the experimental period, the intake of fruitswas limited for the purpose of limiting the intake of pectin as adietary limitation. In addition, the presence or the absence of drugtherapy was also investigated.

The experiment design including the periods of pectin intake and bloodcollection is shown in FIG. 2.

The quantitative measurement method of histamine concentration in plasmawas carried out as described below. 2 ml of blood was collected using anEDTA2K blood collection tube. Within 20 minutes following bloodcollection, the collected blood was centrifuged (4° C., 1500 rpm, 15minutes). 0.5 ml of plasma was dispensed, the resultant was immediatelyfrozen, and it was then used for quantitative measurement of histamine.Histamine was quantitatively measured using a histamine ELISA kit(Immunotech). The average value of histamine concentration for eachperiod is shown in Table 1. A significant difference between the resultsobtained after 3 weeks of intake of pectin granules and those obtainedbefore the start of intake or those obtained 2 weeks after the end ofintake was found through the t-test. TABLE 1 Histamine concentration(ng/ml) t-test Before intake 0.70 P < 0.01 (pectin non-intake) Pectinintake 0.53 After intake 0.67 P < 0.05 (pectin non-intake)

As is clear from the results in Table 1, compared with the resultobtained before the start of the intake of pectin granules, the averagevalue of histamine concentration in plasma measured after the intakesignificantly decreased from 0.70 ng/ml to 0.53 ng/ml (P<0.01).Furthermore, at 2 weeks after the end of intake, the average value ofhistamine concentration in plasma had significantly increased to 0.67ng/ml, which was close to the concentration measured before the intake(P<0.05).

Furthermore, fluctuations in the blood histamine concentrations of eachof all subjects are shown in FIG. 3. 11 out of 14 subjects showeddecreases in histamine concentration due to the intake of pectingranules.

The above results revealed that the intake of pectin lowers histamineconcentration in blood.

EXAMPLE 2 Preparation of Pharmaceutical Composition

With the following composition, tablets were produced by directcompression molding. High methoxyl pectin powder 100 mg Crystallinecellulose 400 mg Lactose 90 mg Hydroxypropylcellulose-L 4 mg Magnesiumstearate 3 mg Total 500 mg

EXAMPLE 3 Preparation of Cream

With the following compounding ratio, cream (cosmetic) was producedaccording to a standard method. (Compounding ratio) High methoxyl pectinpowder 0.5% Stearic acid 8.0% Stearyl alcohol 4.0% Butyl stearate 6.0%Propylene glycol 5.0% Glyceryl monostearate 2.0% Potassium hydroxide0.4% Antiseptic Optimum dose Antioxidant Optimum dose Aromatic OptimumdosePurified water was added to the above composition to 100%.

EXAMPLE 4 Preparation of Food and Drink

Candy with the following composition was produced. High methoxyl pectinpowder 0.5% Sugar 47.5% Starch syrup 49.0% Aromatic 1.0% Water 2.0%

INDUSTRIAL APPLICABILITY

The histamine release inhibitor of the present invention has the effectof lowering histamine concentration in blood, useful for treating and/orpreventing allergic rhinitis, atopic dermatitis, urticaria, bronchialasthma, peptic ulcer, pollinosis, and the like, has high safety, and canbe continuously used for a long period.

All publications, patents, and patent applications cited herein areincorporated herein by reference in their entirety.

1. A histamine release inhibitor, comprising a pectin or a salt thereofor a pectin hydrolysate as an active ingredient.
 2. The histaminerelease inhibitor of claim 1, wherein the pectin is a high methoxylpectin having an esterification degree of 50% or more and 90% or less.3. The histamine release inhibitor of claim 1, wherein the pectin is alow methoxyl pectin having an esterification degree of 3% or more andless than 50%.
 4. The histamine release inhibitor of claim 1, whereinthe pectin hydrolysate is oligogalacturonic acid and/or polygalacturonicacid with a polymerization degree between 2 and
 100. 5. The histaminerelease inhibitor of claim 1, wherein the pectin hydrolysate is anoligosaccharide comprising 1 type or 2 or more types selected from thegroup consisting of galacturonic acid, rhamnose, arabinose, xylose,fucose, and galactose as a constituent.
 6. The histamine releaseinhibitor of any one of claims 1 to 5, which is for preventing and/ortreating allergic rhinitis, atopic dermatitis, urticaria, bronchialasthma, peptic ulcer, and/or pollinosis.
 7. A pharmaceuticalcomposition, comprising the inhibitor of any one of claims 1 to
 6. 8. Acosmetic, comprising the inhibitor of any one of claims 1 to
 6. 9. Foodand drink, comprising the inhibitor of any one of claims 1 to 6.